PROJECT SUMMARY Suicide is an important mental health problem but nowhere is this problem more striking and extreme as it is in American Indian/Alaska Native (AI/AN) and First Nations (FN) people. Although suicide rates vary among AI/AN communities, rates in some communities are almost 10 times the national average. Additionally, U.S. epidemiological studies demonstrate that compared with other U.S. ethnic groups, AI/AN teens and adults have the highest rates of alcohol use disorders (AUDs), that are associated with significant disability and mortality. Thus, studies identifying the risk factors and psychopathological mechanisms for suicide risk and substance use disorders in AI/AN teens and adults are needed to address the substantial health disparities experienced by AI/AN. Yet comprehensive evidence-based studies of suicide risk and AUDs, especially those that include biological measures, are completely lacking in AI/AN and FN people. The overall objective of this research plan is to identify neural mechanisms, as well as individual and community risk factors for alcohol and other substance use disorders and suicidal behaviors (SB) in a community sample of American Indians (AI) residing on rural reservations. Our previous studies have documented a high lifetime prevalence of moderate and severe alcohol use disorders (AUD) (45%) in this group, and have recently identified an excess of suicidal behaviors (>15% attempted) in AI adults. Our data set is unique in that it includes extensive clinical data, psychosocial measures, sleep, electrophysiology and whole genome sequencing data. Using this rich data set we propose to determine whether this group of AI have distal and proximal risk factors and biomarkers (electrophysiological and genetic), that are similar to general population samples described in the literature, or have unique determinants for SB. Since living on a reservation may add particularly unique risk factors for SB in AI we also propose to use state of the art geocoding methodology to obtain new community based data on risk factors for SB. Unique to our approach is our emphasis on the role that high levels of alcohol use and AUDs play in inducing depressive symptomatology, combined with unique environmental conditions on reservations, as critical factors in driving SB. We additionally propose to collect new longitudinal data to follow up on SB over the life span. Finally, we will use data from the existing and expanded cross-sectional cohort studies of teens and adults as well as the new longitudinal retrospective multi-cohort studies to develop comprehensive bio- psychosocial models of AUD and SB. The proposed analyses have the possibility of uncovering important risk and protective factors for SB in this unique high-risk population of AI, as well as identifying developmentally-relevant points of prevention and intervention to reduce the negative impacts of AUD and SB in adolescence and adulthood.